MAP kinases (mitogen activated protein kinases) are ubiquitous proteins involved in varied cell functions.
These proteins ensure intracellular signal transduction: from the surface of the cell to the nucleus. Three major families of MAP kinases (ERK, p38, JNK) have been identified, which correspond to cascade signaling pathways. These signaling pathways play important roles in cell functions: from apoptosis to proliferation, differentiation, or even neuronal plasticity. These functions depend strictly on, firstly, the type of MAP kinase and, for each type of MAP kinase, on its cellular localization.
In order to elucidate the molecular mechanisms governed by ERK signaling pathways and to be able to interfere with this signaling cascade at a given level, it is useful to have specific inhibitors. The compounds currently available: PD98059 (2′-amino-3′-methoxyflavone, a nitrogenous polycyclic inhibitor) and U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenyl-thio)butadiene), are inhibitors specific for MEKs, the kinases upstream of ERKs. However, their action is located upstream of ERKs, thereby resulting in complete inhibition of the activation of the latter and, consequently, of all the downstream substrates, without discrimination among them and without distinction with respect to their cellular localization.
It would therefore be useful to have inhibitors which are highly selective for ERKs and which act downstream, on one or more specific substrate(s) that is (are) cytoplasmic or nuclear, in order to minimize, preferably completely avoid, any related, or even pleiotropic, effect.